The United Kingdom Collaborative Trial of Ovarian Cancer Screening
(UKCTOCS) trial involving 202,000 women has shown that it is possible to
detect ovarian cancer with high sensitivity, specificity, positive
predictive value, acceptability and compliance using a multimodal
screening strategy which combines serum CA125 interpreted using the risk
of ovarian cancer algorithm, transvaginal ultrasound and clinical
assessment.

There was a significant increase in early stage cancers
detected in the multimodal arm compared to women who had no screening.
No other screening strategy has achieved this.

As with other forms of
cancer screening, there was unnecessary surgery but the surgical false
positive rate with multimodal screening was lower than with any other
prospectively evaluated screening strategy for ovarian cancer. One in
four women who underwent surgery had ovarian cancer.

While the multimodal
screening strategy was associated with a reduction in ovarian cancer
deaths on follow up to 14 years, the latter was not definitive and needs
to be confirmed on follow up which is underway. The final results of
this follow-up are expected in 2019.

There is therefore currently
insufficient evidence to recommend ovarian cancer screening in the
general population.

Despite this, if women at general population risk
wish to access multimodal ovarian cancer screening, they should be fully
informed about the risks / benefits including the true and false
positive rates, true and false negative rates, the benefits of a stage
shift, the risk of complications and the uncertainties around potential
impact on lives saved. They need to understand that to achieve the
performance described in UKCTOCS, the entire multimodal screening
strategy needs to be followed.

High risk women, especially those with
BRCA mutations, should consider risk-reducing surgery as the primary
option to manage their ovarian cancer risk.

The results of the United
Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) which used
multimodal screening in the high risk population has been submitted for
publication and is under review. It will in due course be published and
will provide data on the role of ovarian cancer screening in high risk
women who do not wish to undergo, or wish to delay risk-reducing
surgery.

1 Department of Women’s Cancer, Institute for Women’s Health, UCL, London W1T 7DN, UK; 2 University of New South Wales, Sydney, New South Wales 2052, Australia; 3 Medical Research Council Clinical Trials Unit at University College London, London WC2B 6NH, UK; 4 MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, MA 02114, USA; 5 Department of Social Policy, London School of Economics, London WC2A 2AE, UK

*UKCTOCS trialists
**UKFOCSS trialists

Lay summary of the mortality results of UKCTOCS

The mortality results of UKCTOCS, the largest ever ovarian cancer screening trial, were published in The Lancet in December 2015. In the trial women underwent one of two forms of screening (1) multimodal screening (MMS) based on a yearly CA125 blood test interpreted using the Risk of Ovarian Cancer Algorithm (ROCA) followed by an internal (transvaginal) scan and repeat blood test if the result was abnormal (2) ultrasound screening (USS) based on a yearly internal scan which was repeated if the result was abnormal. They were offered between 7-11 annual screens. The ovarian cancer outcomes till 31st December 2014 of women in the screen groups were compared to those of women in the control (C) group who were not offered any screening.

The trial shows for the first time that multimodal screening results in the detection of significantly more earlier stage ovarian/peritoneal cancers than no screening. It may be possible to prevent 1 in 5 (20%) ovarian cancer deaths if women undergo annual multimodal screening (MMS) but this needs to be confirmed on further follow up.

For every woman found to have ovarian cancer on screening, 2 additional women in the MMS group and 10 additional women in the USS arm had surgery where the ovaries were only found to have benign lesions or were normal. The surgical complication rate of these additional operations was around 3.1% (MMS) and 3.5% (USS) which matches the standard complication rate for such surgery. In addition, while screening did not raise anxiety, levels of worry were higher in women who had abnormal results and required additional 2nd line tests. Rarely women had complications related to having a blood test or an internal scan such as pain, bruising or cystitis.

Our data at this point is not sufficient to recommend a National Screening Programme like for breast and cervical cancer. We estimate that further follow-up of approximately four years is required before we can confirm the reduction in deaths. However, we remain hopeful that following this time period we will be able to provide the National Screening Committee with all the information they need to make a decision as to whether the NHS should have an ovarian cancer screening programme.

At this point, some women may wish to seek private screening in the absence of a NHS screening programme. This individual decision will depend upon many factors including a woman's personal risk of ovarian cancer, her views on health and screening and the cost involved. Our advice is that women considering private screening should consider both the benefits and harms involved and make a fully informed decision having taken medical advice. On balance the current evidence suggests that the multimodal screening using the ROCA test has the highest sensitivity for detection of ovarian cancer, the lowest number of false positive results and results in ovarian/peritoneal cancers being picked up at earlier stage. However, one cannot be definitely sure that it saves lives.

The UKCTOCS data provide fresh impetus to continue to pursue screening as an option for reducing mortality in this most lethal of gynaecological cancers. We are greatly indebted to our trial participants, the funding agencies and the many NHS staff who have brought us so far.

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial involving 202,000 women has shown that it is possible to detect ovarian cancer with high sensitivity, specificity, positive predictive value, acceptability and compliance using a multimodal screening strategy which combines serum CA125 interpreted using the risk of ovarian cancer algorithm, transvaginal ultrasound and clinical assessment.

There was a significant increase in early stage cancers detected in the multimodal arm compared to women who had no screening. No other screening strategy has achieved this.

As with other forms of cancer screening, there was unnecessary surgery but the surgical false positive rate with multimodal screening was lower than with any other prospectively evaluated screening strategy for ovarian cancer. One in four women who underwent surgery had ovarian cancer.

While the multimodal screening strategy was associated with a reduction in ovarian cancer deaths on follow up to 14 years, the latter was not definitive and needs to be confirmed on follow up which is underway. The final results of this follow-up are expected in 2019.

There is therefore currently insufficient evidence to recommend ovarian cancer screening in the general population.

Despite this, if women at general population risk wish to access multimodal ovarian cancer screening, they should be fully informed about the risks / benefits including the true and false positive rates, true and false negative rates, the benefits of a stage shift, the risk of complications and the uncertainties around potential impact on lives saved. They need to understand that to achieve the performance described in UKCTOCS, the entire multimodal screening strategy needs to be followed.

High risk women, especially those with BRCA mutations, should consider riskreducing surgery as the primary option to manage their ovarian cancer risk.

The results of the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) which used multimodal screening in the high risk population has been submitted for publication and is under review. It will in due course be published and will provide data on the role of ovarian cancer screening in high risk women who do not wish to undergo, or wish to delay risk-reducing surgery.

Affiliations:1 Department of Women’s Cancer, Institute for Women’s Health, UCL, London W1T 7DN, UK;2 University of New South Wales, Sydney, New South Wales 2052, Australia; 3 Medical Research Council Clinical Trials Unit at University College London, London WC2B 6NH, UK;4 MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, MA 02114, USA;5 Department of Social Policy, London School of Economics, London WC2A 2AE, UK

*UKCTOCS trialists**UKFOCSS trialists

Ovarian cancer is the leading cause of death from gynaecological cancers in the United Kingdom. Majority of the women are diagnosed with bulky disease that has spread beyond the ovary and 60% die within five years of diagnosis.

In this trial over 1.2 million women were invited and 202,638, postmenopausal women aged 50 and above were recruited through thirteen centres in England, Wales and Northern Ireland between 2001 and 2005.

They were randomly assigned to two groups – (1) control group (101,359) who received no screening (to reflect the current situation in the UK) and (2) screen group who had annual screening till December 2011.

The women were screened using two tests - (1) those in the multimodal group (50,640) had a blood test for CA125, a protein which is raised in ovarian cancer.

A mathematical formula called the Risk of Ovarian Cancer algorithm then assigned risk depending of the CA125 trend.

If risk was classified as intermediate or elevated, the volunteer underwent repeat blood tests or a scan. (2) women in the ultrasound group (50,639) had an internal (transvaginal) ultrasound scan of the ovaries.

If an abnormality was seen, the scan was repeated. In both groups women had more extensive testing with referral for surgery if there was persistent abnormality. All participants were followed up for health outcomes using postal questionnaires as well as tracked through the Health and Social Care Information Centre for cancer registrations and deaths.

Funding

MRC - Medical Research Council

NHS R&D - National Health Service Research and Development

Cancer Research UK

The Eve Appeal

INFORMATION FOR PARTICIPANTS

As explained at the time you gave consent to take part, participation is voluntary. You are free to withdraw from the study at any time and do not have to give a reason. This will not affect any future care you receive.

If you wish to receive further information about the study or wish to withdraw, you can do so by contacting:

Currently active non-ovarian malignancy. Women who have a past history of malignancy will only be eligible if (a) they have no documented persistent or recurrent disease and (b) have not received treatment for >12 months.

Women who have had an ovarian malignancy in the past.

Women at high risk of ovarian cancer due to familial predisposition as defined by the eligibility criteria for the UKCCCR Familial Ovarian Cancer Screening Study.

Women participating in other ovarian cancer screening trials

Recruitment

1,243,282 women aged 50-74 identified from Heath Authority age/sex registers were invited between April 2001 and September 2005.

205,090 women attended for recruitment.

202,638 were randomised

101,359 to control arm.

50,640 to multimodal screening.

50,639 to
ultrasound screening.

Screening

Women allocated to the screen arms underwent 7-11 annual screens between April 2001 and December 2011.

Follow Up

Follow up involves the gathering and processing of information required to: (1) accurately identify and classify cases of ovarian, fallopian tube and peritoneal cancer and (2) identify other cancers and diseases so that samples and data could be used in secondary studies where participants have given consent.

This is currently ongoing.

Postal questionnaire: All study participants were sent health questionnaires midway through the trial and in April 2014. We are investigating the possibility of sending a further questionnaire in 2018.

National Health Service Registries: All study participants who gave us permission are flagged through either the Health & Social Care Information Centre (HSCIC) for England and Wales or the Central Services Agency and Northern Ireland Cancer Registry depending upon their place of residence. We send the NHS number, date of birth, name and address details of a participant and the registries send us information that they hold on cancer registration and death.

HSCIC Hospital Episode Statistics (HES): For participants residing in England and Wales we also obtain, from HSCIC, HES records. These typically contain information about dates of in- and out-patient visits to English NHS hospitals, procedures undertaken and diagnosis. As above, we supply NHS number, date of birth, name and address details in order to correctly match participants to HES records. HSCIC process both the data we supply for matching and the data they hold before returning HES data for our participants.

Biobank

Over 500,000 serum samples (single sample taken at recruitment for all 3 groups and then annual serial sample taken from multimodal group

Over 350,000 examination transvaginal ultrasound DICOM images

Trial duration

Routine annual screening: April 2001 - December 2011

Follow-up: Till 2018

Primary outcome analysis: 2014

Principal Investigators

Professor Ian Jacobs

University College
London / University of Manchester / University of New South Wales, Sydney, Australia

CONFERENCES AND MEETINGS

2015

o Gentry-Maharaj A. Population screening for ovarian cancer using CA125 interpreted by the risk of ovarian cancer algorithm, Mucins in Health and Disease (13th International Workshop on Carcinoma-associated Mucins), Cambridge, UK, 21st July 2015

o Menon U. Time series algorithms – what can we learn from UKCTOCS, Ovarian Cancer: Developing Research-Based Public Messaging on Early Detection and Screening, Cold Spring Harbour, New York, 24th Oct 2013